Breast cancer is overwhelmingly the most common malignancy of women. Despite substantial efforts, incidence rates and mortality rates have not changed significantly. New therapeutic approaches are clearly needed. Our goals are to develop new treatment strategies for human breast cancer which are derived from an in depth analysis of cellular and molecular events that control mitogenesis and malignant progression. Specifically, a variety of critical steps involved in the breast cancer process will be examined in detail. In program one information on regulation of gene expression by estrogens as well as regulation of expression of steroid and polypeptide receptors for growth factors will be investigated. Specific focus will be paid to the retinoblastoma gene and its role in breast cancer progression. A series of approaches aimed at interrupting signal transduction pathways that lie between ligand binding to cell surface receptor and specific phenotypic effects leading to malignant progression will be the subject of program area two. In program area three, a series of models which mimic the progression of human breast cancer from the hormone dependent phenotype to hormone unresponsiveness will be further explored along with several approaches geared towards blocking this progression. We have substantial preliminary information that suggests that heparin binding growth factors play an important role in epithelial transformation of human breast cancer. We have designed several strategies to interrupt the activity of these growth factors and their exploitation as antitumor therapies will be explored in program area four. Finally, in program area five we will study the control of invasiveness of breast cancer modulated through cell surface proteases. A series of strategies designed to further understand the cellular and molecular biology of these critical regulators of the metastatic phenotype as well as several approaches to their inhibition will be developed as potential antimetastatic therapies.